Cucurbit[7]uril host-guest complexes and [2]pseudorotaxanes with N-methylpiperidinium, N-methylpyrrolidinium, and N-methylmorpholinium cations in aqueous solution

Article abstract of DOI:10.1039/c2ob27282b

The formations of host-guest complexes between cucurbit[7]uril and a series of N-substituted N-methylpiperidinium, N-methylpyrrolidinium, and N-methylmorpholinium cations in aqueous solution have been investigated using ¹H NMR spectroscopy and electrospray ionization mass spectrometry. Dications comprising the N-methylheterocyclic head groups, bridged by a decamethylene chain, form sequential 1:1 ([2]pseudorotaxanes) and 2:1 host-guest complexes with cucurbit[7]uril. The cucurbituril initially resides over the decamethylene chain, however with further additions of the host molecule a translocation of the hosts to the cationic N-heterocyclic head groups occurs. The order of the magnitude of the cucurbituril host-guest stability constants, determined by competitive ¹H NMR binding experiments, follows the trend in the hydrophobicity of the quaternary ammonium cations.

Full text of DOI:10.1039/c2ob27282b

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Cucurbit[7]uril host–guest complexes and
[2]pseudorotaxanes with N-methylpiperidinium,
N-methylpyrrolidinium, and N-methylmorpholinium
cations in aqueous solution†
Cite this: Org. Biomol. Chem., 2013, 11,
1234
Mona A. Gamal-Eldin and Donal H. Macartney*
The formations of host–guest complexes between cucurbit[7]uril and a series of N-substituted N-methyl-
piperidinium, N-methylpyrrolidinium, and N-methylmorpholinium cations in aqueous solution have been
investigated using 1H NMR spectroscopy and electrospray ionization mass spectrometry. Dications com-
prising the N-methylheterocyclic head groups, bridged by a decamethylene chain, form sequential 1 : 1
([2]pseudorotaxanes) and 2 : 1 host–guest complexes with cucurbit[7]uril. The cucurbituril initially resides
over the decamethylene chain, however with further additions of the host molecule a translocation of
the hosts to the cationic N-heterocyclic head groups occurs. The order of the magnitude of the cucurbit-
uril host–guest stability constants, determined by competitive 1H NMR binding experiments, follows the
trend in the hydrophobicity of the quaternary ammonium cations.
Received 25th November 2012,
Accepted 20th December 2012
DOI: 10.1039/c2ob27282b
www.rsc.org/obc
neutral cyclophane host in CDCl3 at 30 °C.7 Using tetraanionic
cyclophanes in water, the binding in water at 23 °C was
Introduction
The N-alkyl or N-aryl derivatives of morpholine, piperidine, reported to be 250 dm3 mol−1.8 Binding constants of 500–1000
and pyrrolidine are found in a large number of plant alkaloids dm3 mol−1 were determined for the complexation in DMSO at
and drug molecules, including nicotine, minoxidil (Rogaine), 27 °C with partially-bridged deep cavitands.9 The N-methyl-
meperidine (Demerol).1 The steroidal neuromuscular blocking pyrrolidine forms a proton-bound homodimer when encapsulated
agents, such as rocuronium, vecuronium, and pancuronium, in Raymond’s self-assembled supramolecular host [Ga4L6]12−
all contain these N-heterocycles on either end of the steroid (L = N,N′-bis(2,3-dihydroxybenzoyl)-l,5-diaminonaphthalene),
framework.2 The N-methyl derivatives of the heterocycles are while the slightly larger N-methylpiperidine is encapsulated as
used as mimics for trimethylammonium groups and have a protonated monomer.10
recently been investigated as inhibitors for histone readers
The 1,10-bis(N-methylmorpholinium)decane diiodide, 1,10-
which target trimethyllysine.3 The salts of quaternary bis(N-methylpiperidinium)decane diiodide, and 1,10-bis(N-
ammonium N-methyl derivatives of morpholine, piperidine, methylpyrrolidinium)decane diiodide compounds have been
and pyrrolidine have also found applications as ionic liquids4 studied as inhibitors of acetylcholinesterase enzymes11
and as ionic liquid crystals.5
because of their similarities to the widely used drugs deca-
The N,N-dimethylpiperidinium chloride (mepiquat chlor- methonium bromide and succinylcholine. The 1,16-bis(N-
ide) is a systemic plant growth regulator6 and its complexation methylpyrrolidinium)hexadecane dication (G25) has been
by a number of macrocyclic host molecules has been investi- reported to have potent antimalarial activity.12 Keinan and co-
gated in aqueous and non-aqueous media.7–10 This cationic workers have recently utilized diprotonated 1,6-bis(piperidine)-
guest has a stability constant of less than 5 dm3 mol−1 with a hexa-2,4-diyne and 1,6-bis(pyrrolidine)hexa-2,4-diyne guests
to thread the cucurbit[6]uril host molecule, forming
[2]pseudorotaxanes.13
Department of Chemistry, Queen’s University, 90 Bader Lane, Kingston, ON K7L
The cucurbit[n]uril (CB[n], n = 5–8, 10) family of macrocyclic
host molecules,14 comprised of n glycoluril units bridged by
3N6, Canada. E-mail: donal@chem.queensu.ca; Fax: +1 613 533 6669;
Tel: +1 613 533 2617
2n methylene groups, has a hydrophobic inner cavity accessed
through two constrictive polar portals lined with ureido carbo-
nyl groups (Fig. 1). The portals are attractive to cationic guest
†Electronic supplementary information (ESI) available: 13C and 1H–13C HSQC
NMR spectra of guest molecules, representative 1H NMR titration spectra, and
details of stability constant calculations. See DOI: 10.1039/c2ob27282b
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Fig. 1 Structure of cucurbit[7]uril.
molecules through ion–dipole and dipole–dipole interactions,
and combined with the hydrophobic effect, have led to the
determinations of host–guest stability constants (up to 1015
dm3 mol−1 with CB[7]) in aqueous solution which rival that of
the avidin–biotin complex in Nature.15 Cationic guests bearing
ferrocenyl, adamantyl, and bicyclo[2.2.2]octane cores form
these complexes with ultra-high stability by efficient
packing of the cavity16 and the placement of the positive
charges at the portal(s).14,15,17 The complexation of guest
molecules of biological and medicinal interest by CB[7] has
received considerable recent interest,18–21 and the effects of
the complexation on properties of the guest, such as the
aqueous solubility21 and pKa values,19,20 have applications in
molecular recognition and sensing, and drug delivery and con-
trolled release.
Fig. 2 Structures of the cationic guests used in this study. The numbers adja-
cent to the proton positions are the complexation-induced 1H NMR chemical
shift changes (Δδlim) for guests bound to CB[7] in D2O.
We have shown that guests with hydrophobic quaternary
tetraalkylammonium centers,22–24 including those in choline
and acetylcholine,22 can also occupy the inner cavity of cucurbit-
[7]uril with considerable selectivity on the basis of the size
of the cation. We have also recently reported that CB[7] pro-
vides for selective molecular recognition of the important epi-
genetic amino acid marker Nε,Nε,Nε-trimethyllysine (3500-fold)
over lysine itself.24
Dicationic bolaamphiphilic guest molecules have been pre-
pared in our laboratory using trialkylammonium, trialkyl-
phosphonium, pyridinium, and quinuclidinium head groups
and a polymethylene linker group and have been shown to form
[2]pseudorotaxanes with CB[7].25,26 With most of these guests,
the initial complexation by CB[7] is over the polymethylene Fig. 3 Structures of the dicationic guests used in this study. The numbers adja-
cent to the proton positions are the complexation-induced 1H NMR chemical
chain, with additional equivalents of the host molecule result-
ing in a translocation of the original host and the positioning
of the second host onto the cationic head groups at either end
shift changes (Δδlim) for guests bound to CB[7] in D2O, with the numbers on the
left and right sides representing values for the 1 : 1 and 2 : 1 host–guest com-
plexes, respectively.
of the guest.
In this paper, we report the very strong binding between
the macrocyclic host molecule cucurbit[7]uril and protonated
and N-alkylated derivatives of N-methylmorpholine, N-methyl-
Results and discussion
Host–guest complexation between cucurbit[7]uril and
piperidine, and N-methylpyrrolidine (Fig. 2) in aqueous
solution, employing 1H NMR and ESI-MS spectral
monocationic guests
1
techniques. As well, the aforementioned 1,10-bis(N-methyl-
morpholinium)decane, 1,10-bis(N-methylpiperidinium)decane,
and 1,10-bis(N-methylpyrrolidinium)decane dications (Fig. 3)
have been employed as the thread components in the for-
mation of [2]pseudorotaxanes and 2 : 1 host–guest complexes
with CB[7].
The H NMR and ESI-MS spectra of the monocationic guests
(Fig. 2) in the presence of an excess of cucurbit[7]uril in
aqueous solution are consistent with the formation of a
1 : 1 host–guest complex (Table 1). 1H NMR spectroscopy has
proven to be a very useful method for determining the
portion(s) of guest molecules which are located within the
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Table 1 The ESI-MS and 1H NMR spectral data (Δδlim for methyl protons), along with the binding constants for the 1 : 1 host–guest complex between CB[7] and
the monocationic guests in aqueous solution
m/z (obs)
m/z (calcd)
Guest
KCB[7] (dm3 mol−1
(2.3 0.4) × 106 a
(7.8 1.2) × 106 a
(5.0 0.8) × 107 a
(5.1 0.8) × 106 a
(1.7 0.3) × 107 a
(3.7 0.6) × 107 a
)
Δδlim (ppm)
−0.40
HMeMor+
HMePyrr+
HMePip+
Me2Mor+
Me2Pyrr+
Me2Pip+
1264.4360
1264.4354 for C47H54N29O15
1248.4409
1248.4405 for C47H54N29O14
1262.4558
1262.4562 for C48H56N29O14
1278.4505
1278.4608 for C48H56N29O15
1262.4556
1262.4664 for C48H56N29O14
1276.4709
+
+
+
+
+
+
−0.41
−0.38
−0.76
−0.68
−0.60
1276.4718 for C49H58N29O14
NMe4
(1.2 0.4) × 105
(7.9 1.2) × 106 a
−0.72
−0.82
−0.62c
−0.72
−0.74c
−0.70c
−0.64
−0.85c
−0.41c
+ b
MePrMor+
MePrPyrr+
1306.4818
1306.4887 for C50H60N29O15
1290.4870
+
+
(2.1 0.3) × 107 a
1290.4910 for C50H60N29O14
NPr4
(9.0 2.4) × 103
(2.5 0.4) × 107 a
+ b
AMePyrr+
1288.4713
1288.4717 for C50H58N56N29O14
1340.5048
+
(4.9 0.9) × 105 d
+
N(allyl)4
+
1340.5031 for C54H62N29O14
determined using 3-trimethylsilylpropionic-2,2,3,3-d4 acid as a competitor guest. b Ref. 22. c Hα proton resonance.
K
determined
a
1:1
d
1:1
CB[7]
K
CB[7]
using the tetraethylammonium cation as a competitor guest.
hydrophobic cavity as opposed to being positioned adjacent to
the polar carbonyl-lined portals of the cucurbiturils. An
upfield shift in a guest proton resonance (Δδlim = δbound − δfree
)
is indicative of its average position within the cavity, whereas a
downfield shift indicates that the guest proton is near one of
the portals. The limiting chemical shift values, Δδlim, for the
cationic N-heterocyclic guests upon complexation by CB[7] are
given in Fig. 2.
For the protonated N-methylheterocycles (the pKa values for
the HMeMor+, HMePyrr+, and HMePip+ cations are 7.38,27
10.18,28 and 10.08,29 respectively) and the N,N-dimethylhetero-
cycles, all of the guest protons experience an upfield shift,
indicating that the entire guest molecule is encapsulated in
the inner cucurbituril cavity (see ESI, Fig. S14–S16†). For the N,
N-dimethylheterocycles, along with the N-methyl,N-alkyl
derivatives (see Fig. 2 and 4 and ESI, Fig. S18, S19†), the values
of Δδlim for the N-methyl proton resonances (and the α-CH2 of
the propyl substituents) are found in the range of −0.58 to
Fig. 4 1H NMR titration (in D2O with 50 mmol dm−3 acetate buffer, pD = 4.7)
of the N-methyl,N-propylpyrrolidinium cation (1.0 mmol dm−3) with (a) 0.00, (b)
0.21, (c) 0.43, (d) 0.64, (e) 0.90, (f) 1.16, and (g) 2.10 equiv. of CB[7].
−0.84 ppm, similar to the value of −0.72 and −0.69 ppm protonated and alkylated (other than methylated) N-methyl-
and choline22 guests, respectively, heterocycles, the inclusions of these guests within the CB[7]
+ 23
observed for the NMe4
with CB[7], suggesting that the quaternary ammonium center
is located within the CB[7] cavity.
cavity cause the normally rapid chair/chair (morpholinium
(see ESI, Fig. S18†) and piperidinium) and envelope/twisted-
For the protonated N-methylheterocycles, the values of ring (pyrrolidinium, see Fig. 4 and ESI, Fig. S14†) interconver-
sions30 to become sufficiently slow on the NMR timescale such
Δδlim for the methyl proton resonances are considerably
smaller (−0.38 to −0.41 ppm, Fig. 2), suggesting that the less that the axial and equatorial methylene proton signals are
hydrophobic quaternary ammonium center in these guests is observed in the spectra of the host–guest complexes.
closer to the portal. We have previously observed a similar
The proton resonances of the CB[7] host molecule are also
trend in comparing the methyl Δδlim value of Nε,Nε,Nε-tri- affected by the inclusions of the cationic guest molecules.
methyllysine (−0.69 ppm) to those of Nε,Nε-dimethyllysine While the resonances for the methylene proton pointing
(−0.63 ppm) and Nε-methyllysine (+0.06 ppm).24 With the
towards the portals are not changed, the resonance for the
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methylene proton pointing away from the portal and the and Me2Pyrr+ cations, respectively,34,35 correspond to PC
methine proton resonance exhibits downfield shifts of values of 53, 50, and 46%.
0.08–0.10 ppm upon complexations of the cationic guests. A
The MePrMor+, MePrPyrr+, and AMePyrr+ cations contain
similar downfield shift in the resonance for the methylene 10, 9, and 9 heavy atoms, respectively, and their calculated
proton pointing away from the portal was observed upon CB[7] molecular volumes of 154, 137, and 134 Å3, respectively, corre-
complexation of quinuclidiniumchloline. This suggests that spond to PC values of 64, 57, and 55%. The downfield chemi-
tightly fitting quaternary ammonium guests, with the positive cal shift changes for the terminal methyl protons on the
charge within the cavity, result in deshielding of these external propyl substituents of the MePrMor+ and MePrPyrr+ cations
CB[7] protons.
(Fig. 2) suggest that this portion of the guests is located
Linear plots of Δδobs against the [CB[7]] plateau at one outside of the inner cavity of CB[7].
equivalent of the host (see ESI, Fig. S17†), for the monocatio-
Host–guest complexation between cucurbit[7]uril and
dicationic guests
nic guests, indicate the formation of 1 : 1 host–guest complexes
with stability constants which are too large to be accurately
determined from fitting the chemical shift data. Instead, com- Dicationic bolaamphiphilic guest molecules were prepared
petitive 1H NMR binding experiments were carried out for using N-methylpiperidinium, N-methylpyrrolidinium, and
each guest molecule using the protocol of Isaacs and co- N-methylmorpholinium head groups and a decamethylene
workers31 in D2O containing a 50 mmol dm−3 sodium acetate linker group. We have previously investigated similar dicatio-
buffer (pD 4.7). The competing guest was 3-trimethylsilyl- nic guests with CB[7], in which the head groups were
propionic-2,2,3,3-d4 acid (KCB[7] = 1.82 × 107 dm3 mol−1),31 whose trialkylammonium,
trialkylphosphonium,
pyridinium,
methyl proton resonance shifts from 0.00 to −0.68 ppm upon quinuclidinium, and isoquinolinium species (Table 2).25,26,36
complexation by CB[7]. The hereby calculated stability con- With most of these guests, the initial complexation by CB[7]
stants for the monocationic guests are presented in Table 1. involved encapsulation of the decamethylene chain, such that
The trends in the binding constants are a reflection of the each of the positively charged centers would be placed adja-
hydrophobicities of the guests’ N-heterocylic ring, with piper- cent to a polar portal of the cucurbituril, and the formation of
idinium > pyrrolidinium > morpholinium. The ether –O– group a [2]pseudorotaxane.
on morpholinium would be more difficult to desolvate than
Additional equivalents of the host molecule resulted in a
the methylene –CH2– moiety on piperidinium, while the pyrro- translocation of the original host and the positioning of the
lidinium would be less effective in packing the inner cavity of second host onto the cationic head groups at either end of the
CB[7], as discussed below. The nature of the R substituent on guest. An exception to this was in the case of the quinuclidi-
the pyrrolidiniium ring: allyl, propyl, methyl, or hydrogen, has nium head group,25 where the binding to this hydrophobic
a much smaller effect on the stability constant, with the alkyl group was sufficiently strong that the CB[7] simply formed
substituents in the range of (1.7–2.5) × 107 dm3 mol−1
St-Jacques et al. reported that the order of the binding of exclusively to the end groups (Table 2).
.
sequential 1 : 1 and 2 : 1 host–guest complexes with binding
+
+
+
+
the onium guests by CB[7] is NEt4 > NMe4 > NPr4 > NBu4 .
With the three dicationic guests in the present study, a
In this series the trend in the binding follows the hydrophobi- 1 : 1 host–guest complex with CB[7] was observed by ESI mass
city until the guest becomes too bulky to properly accommo- spectrometry (Table 2), and in the case of the MePip-
date all of the alkyl groups in the cavity.23 We observe that the (CH2)10MePip2+ dication, a peak corresponding to the 2 : 1
tetraallylammonium cation (Δδlim = −0.40 (Hα), −0.26 (Hβ), complex was also identified. The 1H NMR titrations with CB[7]
and −0.41 and −0.50 (Hγ) ppm) may bind with a different revealed, through the complexation-induced chemical shift
+
orientation in the cavity than NPr4 (Δδlim = −0.70 (Hα), −0.40 changes in the guest protons, that initial binding is to the deca-
(Hβ), and −0.22 (Hγ) ppm23), providing for a more stable methylene chain, generating a [2]pseudorotaxane. With the
complex with CB[7] (Table 1). In the case of the present set of 1,10-bis(N-methylpyrrolidinium)decane dication (Fig. 5), for
monocationic N-heterocycle guests, the cyclic nature of the example, the Hγ–Hε methylene proton resonances shift signifi-
guest allows it to overcome the bulkiness of the alkyl groups. cantly upfield (fast exchange behaviour), with lesser shifts for
Nau and coworkers16 have recently reported on a study of the the Hα and Hβ resonances, up to one equivalent of CB[7]. The
packing efficiency of hydrocarbon guests within the inner H2 and H3 protons of the pyrrolidinium ring, along with the
cavity of CB[7] (242 Å3) and the results were consistent with the methyl proton resonance, exhibit small downfield shifts owing
calculation of Mecozzi and Rebek32 that a 55–68% packing to their locations outside of the cavity near the portals. In the
coefficient (PC) is ideal. We have recently reported that the case of the 1,10-bis(N-methylmorpholinium)decane dication,
neutral hydrophobic 2-(2,4,4-trimethylpentyl) group on the however, the complexation of the decamethylene chain exhi-
benzethonium cation binds to CB[7] with a stability constant bits slow exchange behaviour on the NMR timescale, with
of 4.1 × 103 dm3 mol−1 33
hydrogen) atoms, and has a packing coefficient of 61%. The morpholinium rings and the decamethylene chain.
.
This group contains 8 heavy (non- resonances for both the free and bound guest protons on the
Me2Pip+ and Me2Mor+ cations possess 8 heavy atoms, while
Further additions of CB[7] to a solution of the [2]pseudo-
the Me2Pyrr+ cation possesses 7 heavy atoms. Calculated mole- rotaxane led to a reversal of the shift of Hγ–Hε protons, ulti-
cular volumes of 128, 120, and 111 Å3 for Me2Pip+, Me2Mor+, mately placing them upfield of their locations in the free
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Table 2 ESI-MS data and binding constants for the 1 : 1 and 2 : 1 host–guest complexes between CB[7] and the dicationic guests in aqueous solution
1:1
m/z obs
m/z (calcd)
K
K
(dm3 mol−1
(dm3 mol−1
)
)
CB[7]
2:1
Guest
CB[7]
MeMor(CH2)10MeMor2+
MePyrr(CH2)10MePyrr2+
MePip(CH2)10MePip2+
752.3330
(752.3335 for C62H84N30O14
736.3375
(736.3386 for C62H84N30O14
750.3542 (750.3542 for C64H88N30O14
(2.5 0.4) × 109 a
(2.3 0.6) × 106 b
(5.2 0.8) × 108 a
(7.2 1.4) × 105 b
(9.2 1.8) × 108 a
(8.6 1.6) × 106 b
(2.6 1.3) × 108
<101
2+
2+
)
)
2+
)
2+
1332.0673 (1332.0272 for C106H130N58O28
)
2+ c
NMe3(CH2)10NMe3
PMe3(CH2)10PMe3
(9.0 1.5) × 107
(6.5 0.5) × 103
(1.4 0.3) × 107
(2.5 0.3) × 102
(1.6 0.2) × 109
(1.6 0.3) × 108
(1.9 0.6) × 1010
(5.6 3.2) × 108
2+ c
2+ c
NEt3(CH2)10NEt3
Iq(CH2)10Iq2+ d
Quin(CH2)10Quin2+ c
a
1:1
b
2:1
K
determined using p-xylenediamine as a competitor guest.
K
determined using 3-trimethylsilylpropionic-2,2,3,3-d4 acid as a
CB[7]
CB[7]
competitor guest. c Ref. 25, Quin+ = quinuclidinium. d Ref. 35, Iq+ = isoquinolinium.
for other decamethylene-bridged dications with CB[7], such as
2+ 25
the acetylcholinesterase inhibitor NMe3(CH2)10NMe3
.
While the stability constants should mainly reflect the hydro-
phobicity of the decamethylene group, the nature of the cat-
ionic end groups would account for the slight variation in the
observed stability constants. There appears to be some corre-
lation between the charge density on the quaternary atom
(N or P) and the magnitude of the binding constant, with the less
hydrophobic and charge-diffuse quaternary centers providing
more stability for the CB[7] [2]pseudorotaxanes (decamethyl-
+
ene terminated by NMe3 binds more strongly than that with
+
NEt3 ),25 through stronger ion–dipole interactions with the car-
bonyl groups on the host’s portals. With the three different
2:1
CB[7]
head groups used on the dications in this study, the K
values are of similar magnitude to the KCB[7] values for the cor-
responding monocationic N,N-dimethylheterocycles. The
piperidinium moiety exhibits the highest K2:1 stability con-
stants in each series, as it is both the most hydrophobic as
well as offering the highest packing coefficient, as discussed
above.
Fig. 5 1H NMR titration (in D2O with 50 mmol dm−3 acetate buffer, pD = 4.7)
of the 1,10-bis(N-methylpyrrolidinium)decane dication (1.0 mmol dm−3) with (a)
0.00, (b) 0.19, (c) 0.37, (d) 0.56, (e) 0.73, (f) 0.99, (g) 1.50, (h) 2.00, (i) 2.32, and
( j) 3.58 equiv. CB[7].
An excellent example of the use of these three N-hetero-
cycles in drug molecules is the series of steroidal neuromuscu-
lar blocking agents (SNMBs) which are employed in tracheal
intubations during surgery.37,38 The most widely used SNMB
today is rocuronium, which has morpholine and N-allylpyrro-
lidinium groups on rings A and D (separated by 10.9 Å, approxi-
mately the same distance as in the dicationic guests in the
present study), respectively, of the steroid framework. The ear-
liest SNMB, pancuronium, utilizes an N-methylpiperidinium
group on each end of the steroid, while a later derivative,
vecuronium, contains an N-methylpiperidinium group and a
piperidine ring on the two ends of the drug. While these
SNMB drugs represent significant improvements over succinyl-
choline in terms of side effects,38 it is still desirable to have
the ability to reverse their effects once the surgical procedures
are complete.39
guest. The pyrrolidinium H2 and H3, the methylene Hα, as
well as the methyl proton resonances shift significantly upfield
of their free guest positions after the addition of the second
equivalent of CB[7] (Fig. 5). The complexation, by the second
equivalent of CB[7], of the N-methylpyrrolidinium head group
results in a repulsion of the original CB[7] over the decamethyl-
ene group, causing its translocation to the N-methylpyrrolidi-
1
nium group on the other end of the dicationic thread. The H
NMR titrations of the 1,10-bis(N-methylmorpholinium)decane
dication and the 1,10-bis(N-methylpiperidinium)decane dica-
tion with CB[7] (see ESI, Fig. S19 and 20,† respectively) reveal
that similar processes are in operation.
The stability constants for the [2]pseudorotaxane formation
(Table 2) with the present dicationic guests are similar in mag-
nitude (107–109 dm3 mol−1) to the values observed previously
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The sodium salt of octakis(6-deoxy-6-S-mercaptopropionyl)- N,N-Dimethylpyrrolidinium iodide ([Me2Pyrr]I)
γ-cyclodextrin (Sugammadex)40 has been approved in Europe
Yield 75%. mp, >300 °C (Lit. 343–344 °C48). 1H NMR δ 2.16 (m,
for the reversal of the effects of these SNMBs, but concerns
over patient allergic sensitivity (including possible anaphylaxic
reactions to the host and host–drug complex41) have prevented
its approval in North America. Investigations are also under-
way to determine if Sugammadex is useful in reversing anaphy-
laxis induced by SNMBs and other highly allergenic drugs.42
Sugammadex binds the rocuronium, vecuronium, and pancur-
onium cations over the steroidal framework, with stability con-
4H, H3), 3.08 (s, 6H, CH3), 3.45 (t, 4H, J = 7.2 Hz, H2) ppm. 13
C
NMR δ 21.7 (C3), 51.6 (CH3), 65.9 (C2) ppm. HR-ESI-MS: calc.
for C6H14N+ (M − I)+ m/z = 100.1126; found 100.1125.
N,N-Dimethylpiperdinium iodide ([Me2Pip]I)
1
Yield 83%. mp. >300 °C (Lit. 346–348 °C49–51). H NMR δ 1.60
(qn, J = 5.8 Hz, 2H, H4), 1.82 (m, 4H, H3), 3.04 (s, 6H, CH3),
3.28 (t, 4H, J = 5.8 Hz, H2) ppm. 13C NMR δ 19.9 (C3), 20.4
(C4), 51.6 (CH3), 62.9 (C2) ppm. HR-ESI-MS: calc. for C7H16N+
(M − I) m/z = 114.1283; found 114.1283.
stants of 2.5 × 107, 1.0 × 107, and 2.6 × 106 dm3 mol−1
,
respectively.43 Very recently, Isaacs and coworkers have
reported that anionic acyclic glycoluril tetramers bind rocuro-
nium, encapsulating the steroid frame, with comparable or
superior stability constants compared to Sugammadex.44 The
monocations investigated in the present study (Fig. 2) are
excellent models for binding of CB[7] to the different terminal
cationic N-heterocyclic groups on the SNMBs, while the di-
cationic threading ligands (Fig. 3) model the distance between
the two cationic sites in the SNMBs and acetylcholinesterase
inhibitors. The stability constants for the binding of CB[7] to
N-alkyl,N-methylheterocycle cations would suggest that the use
of CB[7] as a reversal agent may have an opposite trend in
binding strength: pancuronium > vecuronium > rocuronium,
with complexations of the terminal cationic (alkylated or pro-
tonated) N-heterocyclic groups. Investigations of the CB[7]
complexation of these SNMBs, and other drugs used to reverse
their action, are in progress.
N-Methyl,N-propylmorpholinium bromide ([PrMeMor]Br)
1
Yield 74%. H NMR δ 0.90 (t, 3H, J = 7.3 Hz, Hγ), 1.72 (m, 2H,
(Hβ), 3.09 (s, 3H, CH3), 3.32 (m, 3H, Hα), 3.39 (m, 3H, H2),
3.94 (m, 4H, H3) ppm. 13C NMR δ 10.0 (Cγ), 14.9 (Cβ), 47.0
(CH3), 59.6 (C2), 60.5 (C3), 66.6 (Cα) ppm. HR-ESI-MS: calc. for
C8H18NO+ (M − Br) m/z = 144.1388; found 144.1390.
N-Methyl,N-propylpyrrolidinium bromide ([PrMePyrr]Br)
1
Yield 64%. H NMR δ 0.88 (t, 3H, J = 7.3 Hz, Hγ), 1.72 (m, 2H,
Hβ), 2.12 (m, 4H, H3), 2.95 (s, 3H, CH3), 3.21 (m, 2H Hα), 3.42
(m, 4H, H2) ppm. 13C NMR δ 10.1 (Cγ), 17.0 (Cβ), 21.5 (C3),
48.3 (CH3), 64.4 (C2), 65.7 (Cα) ppm. HR-ESI-MS: calc. for
C8H18N+ (M − Br) m/z = 128.1439; found 128.1436.
N-Allyl,N-methylpyrrolidinium bromide ([AMePyrr]Br)
1
Yield 68%. H NMR δ 2.19 (m, 4H, H3), 3.02 (s, 3H, CH3), 3.50
(m, 4H, H2), 3.94 (d, J = 7.6 Hz, 2H, Hα), 5.66 (d, J = 16.9 Hz,
1H, Hγ), 5.67 (d, J = 10.4 Hz, 1H, Hγ), 6.04 (m, 1H, Hβ) ppm.
13C NMR δ 21.5 (C3), 48.6 (CH3), 63.7 (C2), 65.6 (Cα), 125.5
(Cβ), 128.3 (Cγ) ppm. HR-ESI-MS: calc. for C8H16NO+ (M − Br)
m/z = 126.1283; found 126.1280.
The bromide salts of the 1,10-bis(N-methylheterocycle)
decane dications were prepared by refluxing 13.3 mmol of the
N-methylheterocycle with 3.3 mmol of 1,10-dibromodecane in
5 mL of methanol for 72 hours. The resulting crude solid pro-
ducts were purified by recrystallizations from methanol–ether
mixtures.
Experimental section
Materials
Cucurbit[7]uril was prepared and characterized by the method
of Day et al.45 N-Methylpiperidine, N-methylpyrrolidine,
N-methylmorpholine, 1,10-dibromodecane, methyl iodide,
1-bromopropane, and 1-bromoallene were used as received
(Sigma-Adrich). Tetraallylammonium bromide was a gift from
Dr Andrew Carrier.46
The bromide or iodide salts of the N-alkyl-N-methylhetero-
cycle cations were prepared by heating at reflux a slight excess
of the alkyl halide with the appropriate N-methylheterocycle
(1.0 g) in methanol (8 mL) for 48 hours. For most of the com-
pounds, solids were obtained and were recrystallized from
methanol–ether mixtures. With the bromide salts of N-methyl,
N-propylmorpholinium, N-methyl,N-propylpyrrolidinium, and
N-allyl,N-methylpyrrolidinium, ionic liquids were obtained by
removing the solvent by rotary evaporation.
1,10-Bis(N-methylmorpholinium)decane dibromide ([MeMor
(CH2)10MeMor]Br2)
1
Yield 53%. mp, 220–226 °C. H NMR δ 1.25 (m, 4H, Hε), 1.30
(m, 8H, Hγ and Hδ), 1.77 (m, 4H, Hβ), 3.14 (s, 6H, CH3), 3.45
(m, 12H, H2 and Hα), 4.02 (m, 8H, H3) ppm. 13C NMR δ 20.9
(Cβ), 25.4 (Cγ), 28.2 (Cδ or Cε), 28.3 (Cδ or Cε), 47.0 (CH3), 59.5
(C2), 60.4 (C3), 65.3 (Cα) ppm. HR-ESI-MS: calc. for
C20H42N2O2 (M − 2Br) m/z = 171.1618; found 171.1618.
N,N-Dimethylmorpholinium iodide ([Me2Mor]I)
1,10-Bis(N-methylpyrrolidinium)decane dibromide ([MePyrr
1
(CH2)10MePyrr]Br2)
Yield 87%. mp, 245–248 °C (Lit. 252 °C47). H NMR δ 3.14 (s,
1
6H, CH3), 3.39 (t, 4H, J = 5.0 Hz, H2), 3.93 (m, 4H, H3) ppm. Yield 63%. mp, 265–268 °C. H NMR δ 1.26 (m, 4H, Hε), 1.30
13C NMR δ 51.9 (CH3), 60.7 (C2), 61.1 (C3) ppm. HR-ESI-MS: (m, 8H, Hγ and Hδ), 1.75 (m, 4H, Hβ), 2.14 (s, 8H, H3), 2.96 (s,
calc. for C6H14NO+ (M − I)+ m/z = 116.1075; found 116.1073.
6H, CH3), 3.24 (t, J = 8.4 Hz, 4H, Hα), 3.42 (s, 8H, H2) ppm.
This journal is © The Royal Society of Chemistry 2013
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Organic & Biomolecular Chemistry
13C NMR δ 21.3 (C3), 23 (Cβ), 25.6 (Cγ), 28.2 (Cδ or Cε), 28.3
(Cδ or Cε), 48 (C1), 64.2 (C2), 64.3 (Cα) ppm. HR-ESI-MS: calc.
for C20H42N22+ (M − 2Br) m/z = 155.1669; found 155.1663.
6 A. H. Kamel, T. Y. Soror and F. M. Al Romian, Anal.
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1,10-Bis(N-methylpiperidinium)decane dibromide ([MePip-
(CH2)10MePip]Br2)
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K. N. Raymond and J. Rebek Jr., Proc. Natl. Acad.
Sci. U. S. A., 2009, 106, 10438.
1
Yield 70%. mp, 264–268 °C. H NMR δ 1.26 (m, 4H, Hε), 1.30
(m, 8H, Hγ and Hδ), 1.60 (qn, J = 6.4 Hz, 4H, H4), 1.69 (m, 4H,
Hβ), 1.81 (m, 8H, H3), 2.95 (s, 6H, CH3), 3.36 (m, 12H, H2 and
Hα), ppm. 13C NMR δ 19.6 (C3), 20.6 (C4), 21 (Cβ), 25.6 (Cγ),
28.2 (Cδ or Cε), 28.3 (Cδ or Cε), 47.8 (CH3), 61.1 (C2), 63.4 (Cα)
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12 (a) K. Wengelnik, V. Vidal, M. L. Ancelin, A. M. Cathiard,
J. L. Morgat, C. H. Kocken, M. Calas, S. Herrera,
A. W. Thomas and H. J. Vial, Science, 2002, 295, 1311;
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2+
ppm. HR-ESI-MS: calc. for C22H46N2 (M − 2Br) m/z =
169.1825; found 169.1820.
Methods
The H and 13C NMR spectra were recorded on Bruker Avance
1
400 and 500 spectrometers in D2O. The high-resolution electro-
spray ionization time-of-flight mass spectra were recorded
on a QStar XL QqTOF instrument with an ESI† source. The
host–guest stability constants for the cucurbit[7]uril complexes
with the cationic guests (KCB[7]) were determined by competi-
13 I. Ben Shir, S. Sasmal, T. Mejuch, M. K. Sinha, M. Kapon
and E. Keinan, J. Org. Chem., 2008, 73, 8772.
14 (a) J. Lagona, P. Mukhopadhyay, S. Chakrabarti and
L. Isaacs, Angew. Chem., Int. Ed., 2005, 117, 4922;
(b) K. Kim, N. Selvapalam, Y. H. Ko, K. M. Park, D. Kim and
J. Kim, Chem. Soc. Rev., 2007, 36, 267; (c) L. Isaacs, Chem.
Commun., 2009, 619; (d) E. Masson, X. Ling, R. Joseph,
L. Kyremeh-Mensah and X. Lu, RSC Adv., 2012, 2, 1213.
15 M. V. Rekharsky, T. Mori, C. Yang, Y. H. Ko, N. Selvapalam,
H. Kim, D. Sobransingh, A. E. Kaifer, S. Liu, L. Isaacs,
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1
tive H NMR binding studies at 298 K as described by Isaacs
and coworkers.31 The solutions were prepared in D2O contain-
ing acetate buffer (0.050 mol dm−3 NaOAc-d3/0.025 mol dm−3
DCl) at pD 4.75 with 3-trimethylsilylpropionic-2,2,3,3-d4 acid
(KCB[7] = (1.82 0.22) × 107 dm3 mol−1),31 tetraethylammonium
bromide ((1.0 0.2) × 106 dm3 mol−1),23 or p-xylylenediamine
((1.84
0.34) × 109 dm3 mol−1 31
) (Sigma-Aldrich, used as
received) as the competing guests. For the determinations of
K1:1 the concentration of CB[7] was less than that of the guest
and the competitor, while for K2:1 the CB[7] concentration was
greater than the concentrations of the guest (to ensure com-
plete formation of the 1 : 1 complex) and the competitor.25,26
17 S. Moghaddam, C. Yang, M. Rekharsky, Y. H. Ko, K. Kim,
Y. Inoue and M. K. Gilson, J. Am. Chem. Soc., 2011, 133,
3570.
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664.
19 D. H. Macartney, Isr. J. Chem., 2011, 51, 600.
20 I. Ghosh and W. M. Nau, Adv. Drug Delivery Rev., 2012, 64,
764.
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